Initial physical changes of puberty are not present by age

13 years in girls (or primary amenorhoe at

16y) by age

14 years in boys

Lack of prog. of pub.:M: 4.

5 yr (No complete Pub.)

F:

5 yr (No mense)Prev: 3%

Initial physical changes of puberty are not present by age

13 years in girls (or primary amenorhoe at

16y) by age

14 years in boys

Lack of prog. of pub.:M: 4.

5 yr (No complete Pub.)

F:

5 yr (No mense)Prev: 3%

ClassificationsClassifications Normal variant :

Constitutional delay in growth and puberty Pathologic:

Hypogonadotropic hypogonadism

Hypergonadotropic hypogonadism

Female :Eugonadism (26%) Mullerian Agenesis Vaginal Septum Imperforate Hymen Androgen Insensitivity Syndrome

Normal variant : Constitutional delay in growth and puberty

Pathologic: Hypogonadotropic hypogonadism

Hypergonadotropic hypogonadism

Female :Eugonadism (26%) Mullerian Agenesis Vaginal Septum Imperforate Hymen Androgen Insensitivity Syndrome

Constitutional delay in growth and pubertyConstitutional delay in growth and pubertyA variation of normal

There is often a family history of father being short as a child & experiencing a late pubertal spurt.

Family history of delayed menarche or delayed secondary sexual characteristics

Height <fifth percentile, but growth rate is normal for skeletal age

The bone age is delayed & corresponds to the height age.

Onset of adrenarche is delayed

Although puberty is delayed, the final adult height and sexual development are normal.

A variation of normal

There is often a family history of father being short as a child & experiencing a late pubertal spurt.

Family history of delayed menarche or delayed secondary sexual characteristics

Height <fifth percentile, but growth rate is normal for skeletal age

The bone age is delayed & corresponds to the height age.

Onset of adrenarche is delayed

Although puberty is delayed, the final adult height and sexual development are normal.

Constitutional delay in growth and Constitutional delay in growth and pubertypuberty

The combination of genetic short stature and constitutional delay leads to more profound short stature

Final height is less than predicted

Spontaneous progression into puberty occurs when the bone age reaches

12 to

13 years.

The combination of genetic short stature and constitutional delay leads to more profound short stature

Final height is less than predicted

Spontaneous progression into puberty occurs when the bone age reaches

12 to

13 years.

HypogonadotropicHypogonadotropic hypogonadismhypogonadism CNS disorders :

Tumors (craniopharyngioma, germinoma, glioma, prolactinoma) Congenital malformations Radiation therapy Other causes

Isolated gonadotropin deficiency Kallmann syndrome (anosmia-hyposmia) Other disorders

Multiple pituitary hormone deficiencies Prader-Willi syndrome Laurence-Moon-Bardet-Biedl syndrome

CNS disorders : Tumors (craniopharyngioma, germinoma, glioma, prolactinoma) Congenital malformations Radiation therapy Other causes

Isolated gonadotropin deficiency Kallmann syndrome (anosmia-hyposmia) Other disorders

Multiple pituitary hormone deficiencies Prader-Willi syndrome Laurence-Moon-Bardet-Biedl syndrome

Craniopharyngiomas have a peak incidence in the teenage years and may cause any type of anterior or posterior hormone deficiency.

Craniopharyngiomas usually calcify, erode the sella turcica when they expand, and may impinge on the optic chiasm, leading to bitemporal hemianopsia and optic atrophy.

Germinomas are noncalcifying hypothalamic or pineal tumors that frequently produce HCG, which may cause sexual precocity in boys who are of a prepubertal age (HCG cross-reacts with the LH receptor because of the similarity of structure between LH and HCG).

Other tumors that may affect pubertal development include astrocytomas and gliomas.

Craniopharyngiomas have a peak incidence in the teenage years and may cause any type of anterior or posterior hormone deficiency.

Craniopharyngiomas usually calcify, erode the sella turcica when they expand, and may impinge on the optic chiasm, leading to bitemporal hemianopsia and optic atrophy.

Germinomas are noncalcifying hypothalamic or pineal tumors that frequently produce HCG, which may cause sexual precocity in boys who are of a prepubertal age (HCG cross-reacts with the LH receptor because of the similarity of structure between LH and HCG).

Other tumors that may affect pubertal development include astrocytomas and gliomas.

Isolated Isolated GonadotropinGonadotropin Deficiency Deficiency Kallmann syndrome :This disorder is caused by mutations in the

KAL gene at Xp 22.

3 (X chromosome). The mutation causes the GnRH neurons to remain ineffectually

located in the primitive nasal area, rather than migrating to the correct location at the medial basal hypothalamus as occurs normally.

isolated gonadotropin deficiency with disorders of olfaction. some patients have a decreased sense of smell, others have

abnormal reproduction, and some have both. Olfactory bulbs and olfactory sulci are often absent on MRI. Other symptoms include disorders of the hand, with one hand

copying the movements of the other hand and shortened fourth metacarpal bone, and an absent kidney.

Kallmann syndrome :This disorder is caused by mutations in the KAL gene at Xp 22.

3 (X chromosome).

The mutation causes the GnRH neurons to remain ineffectually located in the primitive nasal area, rather than migrating to the correct location at the medial basal hypothalamus as occurs normally.

isolated gonadotropin deficiency with disorders of olfaction. some patients have a decreased sense of smell, others have

abnormal reproduction, and some have both. Olfactory bulbs and olfactory sulci are often absent on MRI. Other symptoms include disorders of the hand, with one hand

copying the movements of the other hand and shortened fourth metacarpal bone, and an absent kidney.

Idiopathic Idiopathic HypopituitarismHypopituitarism Congenital idiopathic hypopituitarism.

sporadic types are more common X-linked or autosomal recessive

Congenital hypopituitarism may manifest in a male with GH deficiency, with associated gonadotropin deficiency with a microphallus, or with hypoglycemia with seizures, especially if ACTH and GH deficiency occurs as well.

Congenital idiopathic hypopituitarism. sporadic types are more common X-linked or autosomal recessive

Congenital hypopituitarism may manifest in a male with GH deficiency, with associated gonadotropin deficiency with a microphallus, or with hypoglycemia with seizures, especially if ACTH and GH deficiency occurs as well.

HypogonadotropicHypogonadotropic hypogonadismhypogonadism Functional gonadotropin deficiency

Chronic systemic disease :cystic fibrosis, diabetes mellitus, inflammatory bowel disease, and hematologic disease.

Hypothyroidism : inhibits the onset of puberty and delays menstrual periods. Conversely, severe primary hypothyroidism may lead to precocious puberty.

Cushing disease Hyperprolactinemia Anorexia nervosa and malnutrition Psychogenic amenorrhea

Functional gonadotropin deficiency Chronic systemic disease :cystic fibrosis, diabetes mellitus,

inflammatory bowel disease, and hematologic disease. Hypothyroidism : inhibits the onset of puberty and delays

menstrual periods. Conversely, severe primary hypothyroidism may lead to precocious puberty.

Cushing disease Hyperprolactinemia Anorexia nervosa and malnutrition Psychogenic amenorrhea

Functional Functional gonadotropingonadotropin deficiencydeficiency

Weight loss resulting from voluntary dieting, malnutrition, anorexia nervosa or chronic disease leads to decreased gonadotropin function when weight <80% of ideal weight. Primary or secondary amenorrhea frequently is found in affected

girls pubertal development is absent or minimal, depending on the level

of weight loss and the age of onset.. Regaining weight to the ideal level may not immediately reverse the

condition. Athletic amenorrhea: Increased physical activity, even without weight loss , can lead to

decreased menstrual frequency and gonadotropin deficiency (exercise amenorrhea)

when physical activity is interrupted, menstrual function may return.

Weight loss resulting from voluntary dieting, malnutrition, anorexia nervosa or chronic disease leads to decreased gonadotropin function when weight <80% of ideal weight. Primary or secondary amenorrhea frequently is found in affected

girls pubertal development is absent or minimal, depending on the level

of weight loss and the age of onset.. Regaining weight to the ideal level may not immediately reverse the

condition. Athletic amenorrhea: Increased physical activity, even without weight loss , can lead to

decreased menstrual frequency and gonadotropin deficiency (exercise amenorrhea)

when physical activity is interrupted, menstrual function may return.

HypoHypogonadotropicgonadotropic HypogonadismHypogonadism : CM : CM

Adrenarche usually occurs to some degree. Throughout childhood and in early puberty, patients with

hypogonadotropic hypogonadism have normal proportions and growth.

In adulthood, eunuchoid proportions may ensue because their long bones grow for longer than normal, producing an upper-to-lower ratio below the lower limit of normal of 0.

9 and an arm span greater than their

height. If a patient has concurrent GH deficiency, however,

stature is exceptionally short, and the condition may have been diagnosed in infancy with a microphallus.

May be difficult to distinguish from constitutional delay

Adrenarche usually occurs to some degree. Throughout childhood and in early puberty, patients with

hypogonadotropic hypogonadism have normal proportions and growth.

In adulthood, eunuchoid proportions may ensue because their long bones grow for longer than normal, producing an upper-to-lower ratio below the lower limit of normal of 0.

9 and an arm span greater than their

height. If a patient has concurrent GH deficiency, however,

stature is exceptionally short, and the condition may have been diagnosed in infancy with a microphallus.

May be difficult to distinguish from constitutional delay

HyperHypergonadotropicgonadotropic hypogonadismhypogonadism in in BoysBoys

Common: Klinefelter syndrome Anorchia and cryptorchidism Other forms of primary testicular failure : alkylating

chemotherapeutic agents , Radiation of the gonads Sperm preservation is possible in a boy who will undergo

chemotherapy or radiotherapy Rare:

LH Resistance: male phenotype, no male secondary sexual development, gynecomastia, elevated plasma LH levels, and early pubertal plasma testosterone concentrations that did not increase after hCG administration.

partial deficiency of 17-hydroxylase Nephropathic cystinosis

Common: Klinefelter syndrome Anorchia and cryptorchidism Other forms of primary testicular failure : alkylating

chemotherapeutic agents , Radiation of the gonads Sperm preservation is possible in a boy who will undergo

chemotherapy or radiotherapy Rare:

LH Resistance: male phenotype, no male secondary sexual development, gynecomastia, elevated plasma LH levels, and early pubertal plasma testosterone concentrations that did not increase after hCG administration.

partial deficiency of 17-hydroxylase Nephropathic cystinosis

KlinefelterKlinefelter syndrome syndrome Klinefelter syndrome (seminiferous tubular dysgenesis) :

most common cause of testicular failure. The karyotype is 47,XXY, but variants with more X

chromosomes are possible.

incidence :

1 in

500 –

1000 males.

Testosterone levels may be close to normal, at least until mid-puberty, because Leydig cell function may be spared; however, seminiferous tubular function characteristically is lost, causing infertility.

The common observation is that LH levels may be normal to elevated, whereas FSH levels are usually more unequivocally elevated.

Klinefelter syndrome (seminiferous tubular dysgenesis) : most common cause of testicular failure.

The karyotype is 47,XXY, but variants with more X chromosomes are possible.

incidence :

1 in

500 –

1000 males.

Testosterone levels may be close to normal, at least until mid-puberty, because Leydig cell function may be spared; however, seminiferous tubular function characteristically is lost, causing infertility.

The common observation is that LH levels may be normal to elevated, whereas FSH levels are usually more unequivocally elevated.

HyperHypergonadgonad. . hypogonadismhypogonadism in in GirlsGirls Turner syndrome(Syndrome of gonadal dysgenesis and its

variants) Gonadal dysgenesis

Familial and sporadic XX gonadal dysgenesis and its variants

Familial and sporadic XY gonadal dysgenesis and its variants

Other Causes of Primary Ovarian Failure :chemotherapy and radiation

Noonan's Syndrome (Pseudo-Turner's Syndrome, UllrichSyndrome)

FSH Receptor Resistance Galactosemia,congential disorders of glycosylation-

1 (carbohydrate-deficient glycoprotein syndrome type Ia)

Turner syndrome(Syndrome of gonadal dysgenesis and its variants)

Gonadal dysgenesis Familial and sporadic XX gonadal dysgenesis and its

variants Familial and sporadic XY gonadal dysgenesis and its

variants Other Causes of Primary Ovarian Failure :chemotherapy

and radiation Noonan's Syndrome (Pseudo-Turner's Syndrome, Ullrich

Syndrome) FSH Receptor Resistance Galactosemia,congential disorders of glycosylation-

1 (carbohydrate-deficient glycoprotein syndrome type Ia)

Turner syndromeTurner syndrome Turner syndrome : common cause of ovarian

failure and short stature. The karyotype is classically 45,XO, but other

abnormalities of the X chromosome or mosaicism are possible.

The incidence of Turner syndrome is

1 in

2000 to

5000 births.

The features of a girl with Turner syndrome need not be evident on physical examination or by history, and the diagnosis must be considered in any girl who is short without a contributory history.

Turner syndrome : common cause of ovarian failure and short stature.

The karyotype is classically 45,XO, but other abnormalities of the X chromosome or mosaicism are possible.

The incidence of Turner syndrome is

1 in

2000 to

5000 births.

The features of a girl with Turner syndrome need not be evident on physical examination or by history, and the diagnosis must be considered in any girl who is short without a contributory history.

DiagnosisDiagnosis Hx :

chronic or intermittent illnesses growth and development details the patient’s sense of smell. labor and delivery,and birth trauma history Poor linear growth poor nutritional status during the neonatal

period and childhood A growth chart is plotted to represent

graphically the increase in stature and to assess growth velocity from birth (Late onset of growth failure usually indicates a serious condition)

Family history

Hx : chronic or intermittent illnesses growth and development details the patient’s sense of smell. labor and delivery,and birth trauma history Poor linear growth poor nutritional status during the neonatal

period and childhood A growth chart is plotted to represent

graphically the increase in stature and to assess growth velocity from birth (Late onset of growth failure usually indicates a serious condition)

Family history

Height stage of puberty• BP :HTN:

17 α def. Galactorrhea Neurologic examination (optic discs and visual field,

olfaction) The stigmata of gonadal dysgenesis (Turner’s

syndrome) or the small testes and gynecomastia of Klinefelter’s syndrome may suggest one of these diagnoses.

Mental ret.: PWS ,Noonan Sx

Height stage of puberty• BP :HTN:

17 α def. Galactorrhea Neurologic examination (optic discs and visual field,

olfaction) The stigmata of gonadal dysgenesis (Turner’s

syndrome) or the small testes and gynecomastia of Klinefelter’s syndrome may suggest one of these diagnoses.

Mental ret.: PWS ,Noonan Sx

LH and FSH Testosterone /estradiol Measurement of the rise in LH level after

LHRH administration T

4 and prolactin Na,K Progestational Challenge test Bone Age Sonography

LH and FSH Testosterone /estradiol Measurement of the rise in LH level after

LHRH administration T

4 and prolactin Na,K Progestational Challenge test Bone Age Sonography

MRI: Hypogonadotropic hypogonadism (after R/O CDGP)

KARYOTYPE : Hypergonadotropichypogonadism

MRI: Hypogonadotropic hypogonadism (after R/O CDGP)

KARYOTYPE : Hypergonadotropichypogonadism

EugonadismEugonadism(Differential Diagnosis)(Differential Diagnosis)

primary amenorrhea an anatomic defect may be responsible;

presents with normal secondary sexual development without menstruation. the Mayer-Rokitansky-Kuster-Hauser

syndrome congenital absence of the uterus

1 in

4000 to

5000 female births.

imperforate hymen vaginal septum

syndrome of androgen insensitivity

primary amenorrhea an anatomic defect may be responsible;

presents with normal secondary sexual development without menstruation. the Mayer-Rokitansky-Kuster-Hauser

syndrome congenital absence of the uterus

1 in

4000 to

5000 female births.

imperforate hymen vaginal septum

syndrome of androgen insensitivity

AISAIS The complete syndrome of androgen

Insensitivity : normal feminization, absence of pubic or axillary hair primary amenorrhea. all müllerian structures, including ovaries,

uterus, fallopian tubes, and upper third of the vagina, are lacking;

the karyotype is 46,XY intra-abdominal testes.

The complete syndrome of androgen Insensitivity : normal feminization, absence of pubic or axillary hair primary amenorrhea. all müllerian structures, including ovaries,

uterus, fallopian tubes, and upper third of the vagina, are lacking;

the karyotype is 46,XY intra-abdominal testes.

TreatmentTreatment

Depends on the diagnosis and the nature of the disorder.

Patients with constitutional delay in growth and adolescence ultimately have spontaneous onset and progression through puberty.

If a permanent condition is apparent, replacement with sex steroids is indicated. BOYS :Initial therapy: at

13 yr of age ,Begin replacement therapy in

boys with suspected hypogonadotropic hypogonadism by bone age ≤

14 yr

GIRLS : Begin hormonal therapy at 12-

13 yr of age

Depends on the diagnosis and the nature of the disorder.

Patients with constitutional delay in growth and adolescence ultimately have spontaneous onset and progression through puberty.

If a permanent condition is apparent, replacement with sex steroids is indicated. BOYS :Initial therapy: at

13 yr of age ,Begin replacement therapy in

boys with suspected hypogonadotropic hypogonadism by bone age ≤

14 yr

GIRLS : Begin hormonal therapy at 12-

13 yr of age

THERAPY OF CDGP THERAPY OF CDGP If Concerned but not anxious or socially handicapped

adolescent: Reassurance and follow-up (tincture of time) Repeat evaluation (including serum testosterone or estradiol) in

6 mo If Psychosocial handicaps, anxiety, highly concerned:

Therapy for

4 mo with Boys: testosterone enanthate

100 mg IM every

4 wk at 14-14.

5 yr of age,

or overnight transdermal testosterone patch Girls: ethinyl estradiol 5-

10 μg daily by mouth or conjugated estrogens

0.

3 mg daily by mouth or overnight ethinyl estradiol patch at

13 yr of age

No therapy for 4-

6 mo; reevaluate status including serum testosterone or estradiol; if indicated repeat treatment regimen.

If Concerned but not anxious or socially handicapped adolescent: Reassurance and follow-up (tincture of time) Repeat evaluation (including serum testosterone or estradiol) in

6 mo If Psychosocial handicaps, anxiety, highly concerned:

Therapy for

4 mo with Boys: testosterone enanthate

100 mg IM every

4 wk at 14-14.

5 yr of age,

or overnight transdermal testosterone patch Girls: ethinyl estradiol 5-

10 μg daily by mouth or conjugated estrogens

0.

3 mg daily by mouth or overnight ethinyl estradiol patch at

13 yr of age

No therapy for 4-

6 mo; reevaluate status including serum testosterone or estradiol; if indicated repeat treatment regimen.

Girls Initial therapy: ethinyl estradiol

5 μg or conjugated estrogen 0.

3 mg (or less) PO daily for 4-

6 mo or preferably estradiol

transdermally After

6 mo of therapy (or sooner if “breakthrough” bleeding occurs) begin

cyclic therapy: Estrogen: first

21 days of month

Progestagen:12th to 21st day of month (e.g., medroxyprogesteroneacetate

5 mg/day)

Gradually increase dose of estrogen over next 2-

3 yr to conjugated estrogen 0.6-1.

25 mg or ethinyl estradiol 10-

20 μg

daily for first

21 days of month or estradiol patch

Girls Initial therapy: ethinyl estradiol

5 μg or conjugated estrogen 0.

3 mg (or less) PO daily for 4-

6 mo or preferably estradiol

transdermally After

6 mo of therapy (or sooner if “breakthrough” bleeding occurs) begin

cyclic therapy: Estrogen: first

21 days of month

Progestagen:12th to 21st day of month (e.g., medroxyprogesteroneacetate

5 mg/day)

Gradually increase dose of estrogen over next 2-

3 yr to conjugated estrogen 0.6-1.

25 mg or ethinyl estradiol 10-

20 μg

daily for first

21 days of month or estradiol patch

BOYS : Initial therapy: at

13 yr of age, testosterone enanthate (or other long-acting testosterone ester)

50 mg intramuscularly

every month for about

9 mo (6-

12 mo) Over the next

3 to

4 yr: gradually increase dose to adult replacement dose of

200 mg every 2-

3 wk

To induce fertility at appropriate time in hypogonadetropic hypogonadism: pulsatile GnRH or FSH and hCG therapy

Treatment of Delayed Puberty BOYS : Initial therapy: at

13 yr of age, testosterone enanthate (or other long-acting testosterone ester)

50 mg intramuscularly

every month for about

9 mo (6-

12 mo) Over the next

3 to

4 yr: gradually increase dose to adult replacement dose of

200 mg every 2-

3 wk

To induce fertility at appropriate time in hypogonadetropic hypogonadism: pulsatile GnRH or FSH and hCG therapy

All patients with any form of delayed puberty are at risk for decreased bone density; adequate calcium intake is essential.

In hypogonadotropic hypogonadism: to induce ovulation at appropriate time: pulsatile GnRH or FSH and hCG therapy

Subjects with hypergonadotropic hypogonadism, whether Turner syndrome or Klinefelter syndrome, have by definition a primary gonadal problem and are unlikely to achieve spontaneous fertility.

Patients with Turner syndrome have had successful pregnancies after IVF with a donor ovum and endocrine support

All patients with any form of delayed puberty are at risk for decreased bone density; adequate calcium intake is essential.

In hypogonadotropic hypogonadism: to induce ovulation at appropriate time: pulsatile GnRH or FSH and hCG therapy

Subjects with hypergonadotropic hypogonadism, whether Turner syndrome or Klinefelter syndrome, have by definition a primary gonadal problem and are unlikely to achieve spontaneous fertility.

Patients with Turner syndrome have had successful pregnancies after IVF with a donor ovum and endocrine support

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